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Title: Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization
Authors: Fujita, Hiroaki
Tokunaga, Akira
Shimizu, Satoshi  kyouindb  KAKEN_id
Whiting, Amanda L.
Aguilar-Alonso, Francisco
Takagi, Kenji
Walinda, Erik  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-1882-6401 (unconfirmed)
Sasaki, Yoshiteru
Shimokawa, Taketo
Mizushima, Tsunehiro
Ohki, Izuru
Ariyoshi, Mariko
Tochio, Hidehito  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-3843-3330 (unconfirmed)
Bernal, Federico
Shirakawa, Masahiro
Iwai, Kazuhiro  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0001-5620-5951 (unconfirmed)
Author's alias: 藤田, 宏明
徳永, 暉
清水, 覚司
高木, 賢治
佐々木, 義輝
下川, 岳人
水島, 恒裕
大木, 出
有吉, 眞理子
杤尾, 豪人
白川, 昌宏
岩井, 一宏
Keywords: linear ubiquitin chains
LUBAC
LUBAC-tethering motif
HOIP
HOIL-1L
SHARPIN
ubiquitin-like domain
ubiquitin-associated domain
cancer
Issue Date: 24-Apr-2018
Publisher: Elsevier BV
Journal title: Cell Reports
Volume: 23
Issue: 4
Start page: 1192
End page: 1204
Abstract: The linear ubiquitin chain assembly complex (LUBAC) participates in inflammatory and oncogenic signaling by conjugating linear ubiquitin chains to target proteins. LUBAC consists of the catalytic HOIP subunit and two accessory subunits, HOIL-1L and SHARPIN. Interactions between the ubiquitin-associated (UBA) domains of HOIP and the ubiquitin-like (UBL) domains of two accessory subunits are involved in LUBAC stabilization, but the precise molecular mechanisms underlying the formation of stable trimeric LUBAC remain elusive. We solved the co-crystal structure of the binding regions of the trimeric LUBAC complex and found that LUBAC-tethering motifs (LTMs) located N terminally to the UBL domains of HOIL-1L and SHARPIN heterodimerize and fold into a single globular domain. This interaction is resistant to dissociation and plays a critical role in stabilizing trimeric LUBAC. Inhibition of LTM-mediated HOIL-1L/SHARPIN dimerization profoundly attenuated the function of LUBAC, suggesting LTM as a superior target of LUBAC destabilization for anticancer therapeutics.
Description: がんを誘発する酵素の新たなタンパク質間相互作用を解明 --抗がん剤の新たなターゲットを発見--. 京都大学プレスリリース. 2018-04-25.
Rights: © 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
URI: http://hdl.handle.net/2433/230872
DOI(Published Version): 10.1016/j.celrep.2018.03.112
PubMed ID: 29694895
Related Link: http://www.kyoto-u.ac.jp/ja/research/research_results/2018/180425_1.html
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